Article
No placebo effect beyond regression to the mean on the six minute walk test in pulmonary arterial hypertension trials
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Published: | September 6, 2019 |
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Outline
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In drug studies, patients are often included when the disease activity is high. This will make any treatment appear to lessen disease activity, although the improvement is biased by selection. This effect is known as regression towards the mean (RTM) [1]. Pulmonary arterial hypertension (PAH) is a rare disease in which patients suffer from progressive loss of their pulmonary vascular bed leading to elevated pressure in the pulmonary circulation and subsequent right heart failure [2]. Currently there is still an average time from onset of symptoms to diagnosis of several years, given the unspecific symptoms of PAH. As a consequence PAH-patients in studies are more likely to show later disease stages which strengthens the hypothesis of a possible selection bias.
We thus aimed at investigating drug trials in Pulmonary Arterial Hypertension (PAH) using the 6-minute walking distance test (6MWD) as primary outcome for the phenomenon of RTM. An existing registry of 43 open label studies and 23 randomized controlled trials conducted between 1990 and 2009 was used as data source. Data-analysis was carried out for each study arm using standardized pre-post effect sizes of the 6MWD corrected for RTM. From the 43 observational studies 50 different “study arms” (each with individual 6MWD data) could be extracted, while the 25 RCTs consisted of 38 different treatment arms, mainly due to different dosing in parallel groups, plus a corresponding placebo (or control) arm. In the observation studies RTM-adjusted treatment effects varying from 9.9 m to 138.7 m with an overall mean of 48.4 m (95% CI: [32.0; 64.8]). In the verum arms the overall effect was slightly lower with am mean of 33.1 m (95% CI: 26.3; 40.0]). In the placebo arms the overall effect was almost zero with a mean value of -2.6 m (95% CI: [-6.2; 1.1]). As a conclusion we found that regression towards the mean plays only a minor role in PAH-studies. Moreover, placebo effects in the RCTs were neglectably small. Therefore our analysis indicates that results of non-randomized observational studies can be regarded as valid tools for gaining valid clinical effects in patients with PAH.
The authors declare that they have no competing interests.
The authors declare that an ethics committee vote is not required.
References
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- Ostermann T, Willich SN, Lüdtke R. Regression toward the mean – a detection method for unknown population mean based on Mee and Chua’s algorithm. BMC medical research methodology. 2008 Dec;8(1):52.
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- Lai YC, Potoka KC, Champion HC, Mora AL, Gladwin MT. Pulmonary arterial hypertension: the clinical syndrome. Circulation research. 2014 Jun 20;115(1):115-30.